Direct and quantitative evaluation of the major human CYP contribution (fmCYP) to drug clearance using the<i>in vitro</i>Silensomes™ model

Parmentier, Yannick; Pothier, Corinne; Hewitt, Nicola J.; Vincent, Ludwig; Caradec, Fabrice; Liu, Jia; Trancart, Marie-Michèle; Guillet, Fabrice; Bouaita, Belkacem; Chesné, Christophe; Walther, Bernard

doi:10.1080/00498254.2017.1422156

Cited by 21 publications

(17 citation statements)

References 54 publications

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“…The potent inhibition of CYP3A4 and CYP2D6 by iloperidone displays K i values which are situated in the range of the K i values observed for such potent CYP3A4 inhibitors as ritonavir, verapamil or erythromycin (K i = 0.1 − 5 µM) [26], as well as in the range of the therapeutic concentration of the neuroleptic (up to 0.2 μM) [27,28]. Hence, a potent inhibition of CYP3A4 and CYP2D6 by iloperidone observed in vitro in the present study may be expected to occur in vivo, since the K i values calculated for human liver microsomes (0.38 and 2.9 µM, respectively) are close to the presumed concentration range of iloperidone in the liver of psychiatric patients.…”

Section: Discussionmentioning

confidence: 87%

The atypical neuroleptics iloperidone and lurasidone inhibit human cytochrome P450 enzymes in vitro. Evaluation of potential metabolic interactions

2020

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Background The present study aimed at examining the inhibitory effect of two atypical neuroleptics iloperidone and lurasidone on the main human cytochrome P450 (CYP) enzymes in pooled human liver microsomes and cDNA-expressed CYP enzymes (supersomes). Methods The activity of these enzymes was determined by the following CYP-specific reactions: caffeine 3-N-demethylation/ CYP1A2, diclofenac 4′-hydroxylation/CYP2C9, perazine N-demethylation/CYP2C19, bufuralol 1′-hydroxylation/CYP2D6 and testosterone 6β-hydroxylation/CYP3A4, respectively, using HPLC. Results Iloperidone inhibited the activity of CYP3A4 via a noncompetitive mechanism (K i = 0.38 and 0.3 µM in liver microsomes and supersomes, respectively) and CYP2D6 via a competitive mechanism (K i = 2.9 and 10 µM in microsomes and supersomes). Moreover, iloperidone attenuated the activity of CYP1A2 (K i = 45 and 31 µM in microsomes and supersomes) and CYP2C19 via a mixed mechanism (K i = 6.5 and 32 µM in microsomes and supersomes) but did not affect CYP2C9. Lurasidone moderately inhibited CYP1A2 (K i = 12.6 and 15.5 µM in microsomes and supersomes), CYP2C9 (K i = 18 and 3.5 µM in microsomes and supersomes) and CYP2C19 via a mixed mechanism (K i = 18 and 18.4 µM in microsomes and supersomes), and CYP3A4 via a competitive mechanism (K i = 29.4 and 9.1 µM in microsomes and supersomes). Moreover, lurasidone competitively, though weakly diminished the CYP2D6 activity (K i = 37.5 and 85 µM in microsomes and supersomes). Conclusion The examined neuroleptics showed inhibitory effects on different CYP enzymes. The obtained results indicate that metabolic/pharmacokinetic interactions with iloperidone (involving mainly CYP3A4 and CYP2D6) and possibly with lurasidone (involving CYP1A2, CYP2C9 or CYP2C19) may occur during combined therapy.

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Section: Discussionmentioning

confidence: 87%

The atypical neuroleptics iloperidone and lurasidone inhibit human cytochrome P450 enzymes in vitro. Evaluation of potential metabolic interactions

2020

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“…This approach has been carried out in individual laboratories, but in most cases, no standard protocol for the inhibition experiments exists. Biopredic International (Rennes, France) has produced pooled human liver microsomes in which one P450 isoform has been selectively inactivated by a suitable mechanism‐based inhibitor using pre‐incubation methods (Parmentier et al, ). By comparing clearance values in control liver microsomes with those in liver microsomes pretreated with a P450 3A4‐mechanism‐based inhibitor, the contributions made by human P450 3A4 to typical P450 3A4‐dependent substrate oxidations have been determined (Parmentier et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…Biopredic International (Rennes, France) has produced pooled human liver microsomes in which one P450 isoform has been selectively inactivated by a suitable mechanism‐based inhibitor using pre‐incubation methods (Parmentier et al, ). By comparing clearance values in control liver microsomes with those in liver microsomes pretreated with a P450 3A4‐mechanism‐based inhibitor, the contributions made by human P450 3A4 to typical P450 3A4‐dependent substrate oxidations have been determined (Parmentier et al, ). However, although several sets of control and selectively inactivated liver microsomes silenced with mechanism‐based inhibitors have been used to investigate the activities of some P450 isoforms, other major P450s have not been investigated using this approach.…”

Section: Introductionmentioning

confidence: 99%

“…suitable mechanism-based inhibitor using pre-incubation methods (Parmentier et al, 2017). By comparing clearance values in control liver microsomes with those in liver microsomes pretreated with a P450 3A4-mechanism-based inhibitor, the contributions made by human P450 3A4 to typical P450 3A4-dependent substrate oxidations have been determined (Parmentier et al, 2017).…”

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confidence: 99%

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Assessment of multiple cytochrome P450 activities in metabolically inactivated human liver microsomes and roles of P450 2C isoforms in reaction phenotyping studies

Murayama

Yajima

Hikawa

et al. 2017

Biopharm & Drug Disp

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The fraction of substrate metabolized (f ) can be used to estimate drug interactions and can be determined by comparison of the intrinsic clearances (CL ) of victim drugs obtained from inhibited and uninhibited hepatic enzymes Commercially available human liver microsomes were recently developed in which one cytochrome P450 (P450) isoform is selectively inactivated. These inactivated liver microsomes were used to evaluate the roles of P450 2C isoforms in the depletion and oxidation of probe substrates. Determination of CL with sets of control and P450 2C9-inactivated liver microsomes yielded f values of 0.69-1.0 for celecoxib, diclofenac and warfarin. Apparent minor contributions of P450 1A2/2C8/3A4 were seen in depletion assays, yielding ~1 for the sum of the f values. Selectively inactivated liver microsomes were thereby shown to be potentially useful for determining the in vitro f values for major P450 2C9 contributions to substrate oxidations. Metabolite formations from diclofenac and warfarin were suppressed by 62-84% by the replacement of control liver microsomes with P450 2C9-inactivated liver microsomes. R-, S- and racemic omeprazole and troglitazone oxidation activities by liver microsomes at multiple substrate concentrations were suppressed by 26-36% and 22-50%, respectively, when P450 2C19- and 2C8-inactivated liver microsomes were used in place of control liver microsomes. This study provides important information to help elucidate the different roles of P450 isoforms in metabolite formation at different substrate concentrations. The data obtained allow the fractions metabolized to be calculated for victim drugs.

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“…Avoid strong CYP3A4/5 inducers’ (https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202324lbl.pdf). A chemically knocked down HLM has recently been introduced as a commercially available preparation, Silensomes™ (Parmentier et al, ). Silensomes™ are prepared by using mechanism‐based inactivators to inactivate certain CYPs one by one in HLM.…”

Section: Reaction Phenotyping To Identify Victim Ddi Riskmentioning

confidence: 99%

In vitro and in vivo methods to assess pharmacokinetic drug– drug interactions in drug discovery and development

Lu¹,

2020

Biopharm & Drug Disp

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Drug-drug interactions (DDIs) caused by the co-administration of multiple drugs are major safety concerns in the clinic. Several drugs have been withdrawn from the market due to perpetrator or victim DDIs. Strategies have been developed to assess DDI risks early in drug discovery to reduce DDI liabilities. High-to-medium throughput assays are available to identify undesirable scaffolds and to guide structural modifications to minimize DDIs. Definitive methods are used at later stages of drug discovery and development to provide a more accurate measurement of DDI parameters and to enable clinical translations. Physiologically based pharmacokinetic modeling and simulations are powerful tools to accurately predict DDIs and to assess risks in the clinic. Although significant advances have been made over the years, many challenges remain for clinical DDI translations. This includes DDIs involving non-cytochrome P450 enzymes, transporters, enzyme-transporter interplay, indirect effects from biologics, and pharmacodynamic based DDI. This review focuses on methods that are used to assess hepatic DDIs caused by enzyme inhibition and induction.

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Direct and quantitative evaluation of the major human CYP contribution (fmCYP) to drug clearance using thein vitroSilensomes™ model

Cited by 21 publications

References 54 publications

The atypical neuroleptics iloperidone and lurasidone inhibit human cytochrome P450 enzymes in vitro. Evaluation of potential metabolic interactions

The atypical neuroleptics iloperidone and lurasidone inhibit human cytochrome P450 enzymes in vitro. Evaluation of potential metabolic interactions

Assessment of multiple cytochrome P450 activities in metabolically inactivated human liver microsomes and roles of P450 2C isoforms in reaction phenotyping studies

In vitro and in vivo methods to assess pharmacokinetic drug– drug interactions in drug discovery and development

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